Healthy Volunteers
Conditions
Brief summary
Purpose: This study aims to evaluate the effect of food (high-fat, high-calorie meal) on the pharmacokinetic (PK) profile of CS0159 tablets and to assess the drug-drug interactions (DDI) when CS0159 is co-administered with a strong CYP3A4 inducer (rifampicin) and a strong CYP3A4 inhibitor (itraconazole), respectively. Design: Part A (DDI - Induction): Single-center, open-label, fixed-sequence design. Sixteen healthy participants will receive a single dose of CS0159 (4 mg) under fasting conditions on Day 1, rifampicin alone (600 mg, QD) under fasting conditions on Days 2-8, and co-administration of CS0159 with rifampicin under fasting conditions on Day 9. Part B (Food Effect & DDI - Inhibition): Single-center, open-label, two-phase design. Sixteen healthy participants will first undergo a randomized, two-period, two-sequence crossover food effect study (CS0159 4 mg administered under fasting vs. high-fat meal conditions). All participants will then enter the second phase, receiving itraconazole (200 mg, QD) after a meal for 5 consecutive days, followed by co-administration of CS0159 with itraconazole after a high-fat meal on the 6th day. Endpoints: The primary endpoints are the pharmacokinetic parameters of CS0159 (C\ max, AUC\ 0-t, AUC\ 0-∞)and other PK parameters (Tmax，t1/2，λz，AUC\_%Extrap，Tlag，CL/F，V/F). Secondary endpoints include safety (adverse events, vital signs, laboratory tests, etc.) .
Detailed description
1. Study Background: CS0159 is a novel farnesoid X receptor agonist under development for the treatment of diseases such as nonalcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Preclinical studies indicate that CS0159 is primarily metabolized by the CYP3A4 enzyme. According to relevant guidelines, it is necessary to evaluate the impact of CYP3A4 modulators (rifampicin and itraconazole) on the exposure of CS0159, as well as the effect of food on its pharmacokinetics, to guide safe clinical use. 2. Study Design and Methods: Overall Design: The study consists of two independent parts (Part A and Part B), planning to enroll a total of 32 healthy adult participants (both sexes) aged 18-45. Part A - DDI Study with Rifampicin: A fixed-sequence design is employed. Participants, under fasting conditions, sequentially receive CS0159 monotherapy, rifampicin monotherapy (for 7 consecutive days), and then co-administration of both drugs. Intensive blood sampling is performed for PK analysis. Part B - Food Effect and DDI Study with Itraconazole: Phase 1 (Food Effect): A randomized, open-label, two-period, two-sequence crossover design is used. Participants are randomly divided into two groups to receive a single dose of CS0159 under fasting and high-fat meal conditions, respectively, with a 2-day washout period between the two periods. Phase 2 (DDI Study with Itraconazole): All participants who complete Phase 1 enter this phase. Participants first receive itraconazole after a meal for 5 consecutive days, followed by co-administration of CS0159 with itraconazole after a high-fat meal. Pharmacokinetic and Safety Assessments: Blood samples are collected at scheduled time points during all CS0159 dosing periods (monotherapy or co-administration). CS0159 plasma concentrations are determined using a validated LC-MS/MS method. Throughout the study, adverse events, vital signs, physical examinations, 12-lead ECGs, and laboratory test results are continuously monitored and recorded. 3. Statistical Methods: Pharmacokinetic parameters will be calculated using non-compartmental analysis. For DDI analysis, analysis of variance will be performed on log-transformed C\ max\ and AUC values, and geometric mean ratios with their 90% confidence intervals will be calculated. Food effect analysis will employ a crossover design analysis of variance. Safety data will be summarized using descriptive statistics.
Interventions
DRUGCS0159 Tablet
A novel, selective farnesoid X receptor (FXR) agonist.
A strong cytochrome P450 3A4 (CYP3A4) enzyme inducer.
A strong cytochrome P450 3A4 (CYP3A4) enzyme inhibitor.
Sponsors
Cascade Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
This is an open-label study. No blinding was used.
Intervention model description
This is a two-part, hybrid-design pharmacokinetic study: 1. Part A (n=16): A single-group, fixed-sequence study. All participants receive CS0159 monotherapy (Day 1), followed by rifampicin alone (Days 2-8), and then co-administration of both drugs (Day 9) to assess the inducing effect of rifampicin on CS0159. 2. Part B (n=16): This part consists of two sequential phases within the same cohort: * Phase 1 (Food Effect):\*\* A randomized, two-period, two-sequence crossover study. Participants are randomized to receive CS0159 either under fasting conditions or after a high-fat meal in the first period, and then cross over to the opposite condition in the second period after a washout. * Phase 2 (DDI with Itraconazole):\*\* Following Phase 1, all participants enter a single-group, fixed-sequence study. They receive itraconazole alone for 5 days, followed by co-administration of CS0159 with itraconazole to assess the inhibitory effect.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female participants aged between 18 and 45 years (inclusive); 2. Male weight ≥ 50.0 kg, female weight ≥ 45.0 kg; body mass index (BMI) within the range of 19.0 to 26.0 kg/m² (including the threshold values); 3. Normal renal function (glomerular filtration rate calculated using the CKD-EPI equation ≥ 90 mL/min/1.73 m²); 4. Participants (including male participants) agree to have no plans for conception from screening until 3 months after the last dose, voluntarily adopt effective contraceptive measures, and have no plans for sperm or egg donation; 5. Participants fully understand the study purpose, nature, procedures, and potential adverse events, voluntarily agree to participate as subjects, can communicate well with the investigator, comply with all study requirements, and sign the informed consent form before the initiation of any study procedures.
Exclusion criteria
1. History of allergic diseases (e.g., asthma, urticaria, eczema, etc.), allergic constitution (e.g., allergy to two or more drugs), or known hypersensitivity to CS0159, rifampicin, itraconazole, or any excipients; 2. Participants with clinically significant findings, as judged by the investigator, of the following diseases (including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, pulmonary, immunological, psychiatric, or cardiovascular/cerebrovascular diseases) that may complicate protocol implementation or interpretation of study results, or whom the investigator considers to be at risk from participating in the study; 3. History of susceptibility to pruritus, or presence of conditions such as eczema/atopic dermatitis, neurodermatitis, psoriasis, or other diseases that may cause pruritus; 4. History of corrected QT interval (QTc) prolongation at screening: 1. QTc interval prolongation on 12-lead electrocardiogram (ECG) (QTcF ≥450 ms in males; QTcF ≥470 ms in females); 2. Family history of hypocalcemia or long QT syndrome. 5. History of acute or chronic bronchospasm (including treated or untreated asthma, chronic obstructive pulmonary disease); 6. Occurrence of an acute illness within 2 weeks prior to the first dose; 7. Presence of any known disease or condition that may interfere with drug absorption, distribution, metabolism, or excretion, including bile salt metabolism in the large intestine. Examples include inflammatory bowel disease, gastrectomy, cholecystectomy, etc.; 8. Use of drugs affecting hepatic metabolic enzyme function (e.g., barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole, SSRIs, cimetidine, diltiazem, macrolides, nitroimidazoles, sedative-hypnotics, verapamil, fluoroquinolones, antihistamines) within 30 days prior to the first dose, or requirement for concomitant use of other drugs that may affect the absorption, distribution, metabolism, or excretion of the investigational drug during the study period; 9. History of blood donation within 3 months prior to the first dose, total blood loss ≥400 mL due to donation or other reasons within 6 months, or plans to donate blood during the study or within 3 months after study completion; 10. Current smokers, or participants unwilling to discontinue nicotine product use from 3 months before screening and during the study, or with positive urine cotinine test results; 11. Excessive consumption of tea, coffee, or caffeinated beverages (more than 8 cups per day, 1 cup = 250 mL) within 6 months prior to screening; or consumption of any food or beverage rich in caffeine and/or xanthine (e.g., coffee, strong tea, chocolate, caffeinated carbonated beverages, cola, etc.) from 48 hours before the first dose until the end of the study; or unwillingness to abstain from alcohol, fruit juice beverages, strenuous exercise, or other factors that may affect drug absorption, distribution, metabolism, or excretion; 12. Average weekly alcohol consumption exceeding 14 units (1 unit = 360 mL beer, 45 mL of 40% alcohol liquor, or 150 mL wine) in the past year, or inability to abstain from alcohol during the study, or alcohol breath test result \>0.0 mg/100 mL; 13. Drug abusers or participants with positive results on drug abuse screening (morphine, tetrahydrocannabinol acid, methamphetamine, methylenedioxymethamphetamine, ketamine, and cocaine); 14. Participation in another drug clinical trial within 3 months prior to this study (Note: The end date is defined as the date of discontinuation from the most recent clinical trial involving drugs or devices); 15. Positive screening results for hepatitis C virus antibody, hepatitis B surface antigen, HIV antibody, or syphilis treponemal antibody; abnormal liver function: AST, ALT, ALP, GGT, and TBil \> upper limit of normal (ULN); 16. Abnormal and clinically significant findings on physical examination, vital signs, laboratory tests, 12-lead ECG, or abdominal ultrasound at screening, as judged by the investigator; 17. Use of prescription or over-the-counter medications within 14 days prior to the first dose or within at least 5 half-lives (whichever is longer); 18. Use of any drugs or substances (e.g., herbal medicines, grapefruit, etc.) that may affect CYP3A activity within 14 days before taking the study drug and during the study period; 19. Difficulty swallowing, intolerance to venipuncture/indwelling needles, difficulty with blood sampling, history of needle or blood phobia, special dietary requirements, or inability to comply with standardized meals; 20. Any other conditions deemed unsuitable for participation by the investigator. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of CS0159 | Day 1, Day 3, Day 9 | Maximum observed plasma concentration (Cmax) of CS0159 |
| AUC0-t of CS0159 | Day 1, Day 3, Day 9 | Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t) of CS0159 |
| AUC0-∞ of CS0159 | Day 1, Day 3, Day 9 | Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of CS0159 |
| Tmax of CS0159 | Day 1, Day 3, Day 9 | Time to reach Cmax (Tmax) |
| t1/2 of CS0159 | Day 1, Day 3, Day 9 | terminal elimination half-life (t1/2) |
| CL/F of CS0159 | Day 1, Day 3, Day 9 | apparent oral clearance (CL/F) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (TEAEs) | From screening until 7 days after the last dose. | Observe all adverse medical events occurring in participants during the clinical study period, including clinical symptoms and clinically significant abnormalities in vital signs, physical examinations, laboratory tests, and electrocardiograms. Record their clinical manifestations, severity, time of onset, time of resolution, duration, management measures, outcomes, and assess their relationship to the investigational product. |
Contacts
CONTACTRong Deng
PRINCIPAL_INVESTIGATORYun Liu
Shanghai Xuhui District Central Hospital
Outcome results
None listed